Drosophila melanogaster as a model for human intestinal infection and pathology

Abstract

Recent findings concerning Drosophila melanogaster intestinal pathology suggest that this model is well suited for the study of intestinal stem cell physiology during aging, stress and infection. Despite the physiological divergence between vertebrates and insects, the modeling of human intestinal diseases is possible in Drosophila because of the high degree of conservation between Drosophila and mammals with respect to the signaling pathways that control intestinal development, regeneration and disease. Furthermore, the genetic amenability of Drosophila makes it an advantageous model species. The well-studied intestinal stem cell lineage, as well as the tools available for its manipulation in vivo, provide a promising framework that can be used to elucidate many aspects of human intestinal pathology. In this Perspective, we discuss recent advances in the study of Drosophila intestinal infection and pathology, and briefly review the parallels and differences between human and Drosophila intestinal regeneration and disease.

Fig. 1.

Similarities between the mammalian and Drosophila intestines. There is similarity between the esophagus and the foregut (blue), the stomach and the crop (yellow), the small intestine and the midgut (green), and the large-intestine–rectum–anus and the hindgut-rectum-anus (gray) in mammals and Drosophila. Differences include the presence of the fly kidney-like malpighian tubules, which empty into the gut, the rectal papillae (red), which are used for water absorption (not present in mammals), and the fly Fe/Cu cells, which are found in a region of low pH that seems to be functionally distinct from the low-pH stomach of mammals.

Fig. 2.

Mammalian intestinal crypts and villi, and the Drosophila midgut, in healthy and diseased animals. (A,B) Healthy and diseased mammalian intestinal crypts are shown made up of green, yellow and orange cells, and villi are shown made up of orange cells. (A) ISCs (green) and Paneth cells (orange) are located in the bottom of the crypts in healthy tissue. TA cells produced by ISCs move upwards while gradually maturing (black arrows). (B) High levels of ISC division owing to inflammation or a genetic predisposition create an overabundance of TA cells that move upwards (green arrows), causing crypt enlargement. (C,D) Healthy and diseased Drosophila midgut. Paneth cells are not present in flies, but ISCs are located basally in fly midgut epithelium. As in the mammalian gut, transient and/or differentiating cells (yellow) are consistently adjacent to ISCs and mature enterocytes (orange). ISCs of the Drosophila midgut are found basally in the epithelium and the transient cells that they produce (enteroblasts) move upwards (black arrows) before growing to their mature size in healthy tissue. (D) Similarly to human intestinal disease, in the Drosophila midgut, infection, aging or genetic predisposition can lead to overproduction of differentiating cells that move basolaterally (infection, aging) or even upwards (e.g. in Wg and Ras1 overexpression) (green arrows), in which case multilayering and tissue dysplasia ensues. (E) x-z section of an infected and genetically predisposed Drosophila gut for a Ras1 oncogene. ISCs or progenitor cells (green) spread out in the epithelium and additional layers of cells (nuclei in blue) protrude into the lumen (green arrows). Also, the lateral junction protein Armadillo (red) is subcellularly mislocalized, expanding from the lateral to the apical side of ISCs or progenitor cells.

Fig. 3.

ISC lineages of mammalian intestine and Drosophila midgut, and the common pathways that control them. Apart from the Wnt/Wg and STAT pathways that are necessary for ISC division, additional similarities between the mammalian and Drosophila midgut ISCs have been noted. For example, midgut ISCs divide when the InR pathway is activated (i.e. following drug exposure) and in the presence of PVF growth factors (during aging); the analogous INSR and PDGF pathways, respectively, control mouse ISC homeostasis. In addition, ISCs are controlled by the Notch pathway; however, Notch activates ISC proliferation in mammals but causes them to differentiate in Drosophila midgut. Nevertheless, Notch signaling is similarly required for the specification of enterocyte (EC) versus secretory (Sec) fate during the commitment of TA cells and enteroblasts (EBs). Wnt/Wg, which is needed for determination of secretory cell fate differentiation in mammals, is apparently not crucial for similarly specifying cell fate in the fly midgut.

Fig. 4.

Identifying cell types in the Drosophila posterior midgut using available tools. Visualization of ISCs or progenitor cells (using esg-lacZ; blue), enteroendocrine cells (using anti-Prospero; red) and enterocytes (using myo-GAL4 UAS-GFP; green) to distinguish the three cell types in the Drosophila posterior midgut.